Focusing on Rare Variants Related to Maturity-Onset Diabetes of the Young in Children

Abstract

Background: In this study, we analysed the clinical and genetic characteristics and follow-up data of patients with maturity-onset diabetes of the young (MODY). Methods: From January 2015 to December 2022, patients with persistent hyperglycaemia suspected of having monogenic diabetes or diabetes syndrome were recruited, and next-generation sequencing (NGS) was performed at the Shanghai Children's Medical Center. Patients' clinical and laboratory findings were recorded preceding follow-ups. Candidate variants were verified using Sanger sequencing. Variant pathogenicity was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Genetic testing was performed in 175 children. MODY-related pathogenic or likely pathogenic gene variants were identified in 30 patients from different families. Of these, 11 were diagnosed with GCK-MODY (36.7%), six with INS-MODY (20%), five with HNF1A-MODY (16.7%), five with ABCC8-MODY (16.7%), two with HNF1B-MODY (6.7%) and one with HNF4A-MODY (3.3%). There was one shift variant and seven splice-site variants, and the rest were missense variants. We discovered six novel variants. Of the 30 patients, 63.3% had a family history of diabetes, 13.3% had diabetic ketoacidosis (DKA), and 16.7% had positive diabetes-associated autoantibodies. The diabetes phenotype of patients with the INS variant was similar to that of patients with type 1 diabetes. All patients, including those having positive autoantibodies, required long-term insulin therapy during follow-ups. Four patients with the ABCC8 variant were unable to switch to oral sulfonylurea therapy and continued insulin therapy. Conclusion: Genetic testing is helpful for the precise diagnosis and treatment of patients with MODY, including those with DKA history and positive diabetes autoantibody. GCK-MODY is the most common type of MODY, and patients with INS variant account for a relatively large proportion of MODY cases in our cohort.

Keywords: MODY; childhood; next-generation sequencing; rare subtypes.

Figure 1

The flow chart of patient recruitment. Among the 571 patients, genetic investigations were performed in 175 patients who met the inclusion criteria. Thirty patients with maturity-onset diabetes of the young (MODY) from different families were identified and included in the final analysis.

Figure 2

Genetic characteristics of patients with MODY. (A) Distribution of detected gene variants associated with MODY. (B) Distribution of the variants newly discovered in our cohort. (C) Location of the variants found in patients with INS-MODY. MODY, maturity-onset diabetes of the young.

Figure 3

Clinical characteristics of patients with MODY. (A) Distribution of diagnosis age. (B) Distribution of BMI. (C) Distribution of HbA1c. (D) Distribution of fasting glucose and C-peptide. (E) OGTT of five patients with INS-MODY. (F) OGTT of 10 patients with T1DM with diabetes autoantibody positive. BMI, body mass index; HbA1C, glycosylated haemoglobin; MODY, maturity-onset diabetes of the young; OGTT, oral glucose tolerance testing; T1DM, type 1 diabetes mellitus.